A [bmim]Cl-promoted domino protocol using an isocyanide-based [4+1]-cycloaddition reaction for the synthesis of diversely functionalized 3-Alkylamino-2-Alkyl/aryl/hetero-Aryl indolizine-1-carbonitriles under solvent-free conditions

Article abstract of DOI:10.1039/c9nj05738b

A domino protocol involving aldehydes, isocyanides and 2-pyridylacetonitrile in the presence of [bmim]Cl as a promoter and solvent for the synthesis of 3-Alkylamino-2-Alkyl/arylindolizine-1-carbonitriles is described. A wide range of alkyl, aryl and heter

Full text of DOI:10.1039/c9nj05738b

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DOI: 10.1039/C9NJ05738B
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[bmim]Cl: Promoted domino protocol of isocyanides-based [4 + 1]-
cycloaddition reaction for the synthesis of diversely functionalized
3-alkylamino-2-alkyl/aryl/hetero-aryl
under solvent free condition.
indolizine-1-carbonitrile
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Amol Balu Atar*a, Jongmin Kanga, and Arvind H. Jadhavb
A
domino protocol of aldehydes, isocyanides and 2- transition-metal-catalyzed intramolecular cycloisomerization,12
pyridylacetonitrile in presence of [bmim]Cl as a promoter and cyclocondensations,13 cycloadditions,14
solvent for the synthesis of 3-alkylamino-2-alkyl/arylindolizine-1- cyclization/elimination15 and multicomponent coupling
carbonitrile is described. A wide range of alkyl, aryl and hetero-aryl reactions.16 However, the most reported methods have several
aldehydes reacted with 2-pyridylacetonitrile and isocyanides, drawbacks, due to the limited scope, harsh reaction conditions,
leading to an indolizine derivatives with high selectivity, high atom require the use of transition-metal catalysts and additives, and
economy, and good to excellent yields. These straight forward and involve tedious work-up processes and long reaction times,
highly efficient method allows the synthesis of bis indolizine-1- which strongly affect the economics as well as the
carbonitrile derivatives.
environmentally friendly nature of the reaction.
Introduction
OH
O
CN
Cl
N
N
N
Fused indolizines, which are most representative N-fused
heterocyclic compounds, having potential application in the
field of medicinal chemistry and organic synthesis.1 The
biological activities of fused indolizines nucleus have been
discovered in the form of anticancer,2 anti-inflammatory,3
antimicrobial,4 anti-tubercular,4 antifungal,5 antioxidant,6 and
inhibitor for vascular endothelial growth factor (VEGF).7
O
HN
CN
Ph
Endothelial growth factor (VEGF)
Anti-bacterial agent
R2
Anti-fungal
R2
R1
O
N
N
N
O
R3
H2N
Especially,
the
3-substituted
indolizine-1-carbonitrile
O
N
derivatives exhibited activity against phosphatase inhibitors.8
Apart from medical application, the fused indolizines nucleus
has also displayed more newly distinctive fluorescent and
photophysical properties which provide new potential
applications in materials science.9 Furthermore, fused
indolizines nucleus act as herbicides and fungicides in the
agricultural sector.10,11 Examples of some active substituted
indolizines are depicted in Figure 1.
Due to the broad range of applications, the significant interest
extend on this specific skeleton has led to substantial
development of numerous elegant approaches for the
expeditious assembly of the indolizine core. These includes
R
R1
C3 Indo-Fluor
Anti-cancer
Seoul-Fluor (SF)
Figure 1. Selected examples of active indolizines.
Recently, multicomponent coupling reactions (MCRs) have
emerged as powerful and versatile synthetic tools for the
organic chemist in the field of modern organic chemistry and is
one of the popular research areas of the scientific community
that drives increasing efforts.17 MCRs have been considered and
used as one of the most important tools for the construction of
novel and structurally complex molecules in a single pot
ensuring high efficiency, safe, high selectivity, atom- and step-
economical synthesis strategy.18 Recently, isocyanide-based
multicomponent reactions followed by other synthetic
conversions emerged as a powerful tool for designing fused
multicyclic skeletons.19 Therefore, the development of novel
protocol with MCRs approaches continues to attract the
attention of organic chemists.20 In addition, currently attention
focused on the replacement of volatile organic solvents by
aDepartment of Chemistry, Sejong University, Seoul 143-747, South Korea
bCentre for Nano and Material Science(CNMS), Jain University, Jain Global Campus,
Bangalore 562112, Karnataka, India
*E-mail: amol.atar@sejong.ac.kr
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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environmentally friendly solvents in organic synthesis.21 In this further by using similar condition, the reaction was carried out
View Article Online
context, room temperature ionic liquids (RTILs) is the most at various temperatures. These results sDhOowI: 1s0.t1h0a3t9/tCh9eNrJe05is73n8oB
convenient eco-friendly solvent due to unique properties such any product formation and indicated that need promoter to
as nonvolatility, thermal stability, solvation ability, and easy accomplish the reaction (Table 1, entries 2, 3, 4).
recyclability.22 Importantly, RTILs may play a dual role as both Table 1 Screening of various types of promoters and solvents
a
catalysts and solvents in the organic synthesis.23 With these for the synthesis of compound 4a
O
H
aspects of green metrics in mind, the development of catalyst-
free, RTILs promoted multicomponent reactions in
environmentally benign media would be of considerable
interest.
10
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CN
N
Condition
N
C
CN
N
N
H
Cl
On the basis of the above analysis and continuing our research
program on the sustainable synthesis of biologically active
heterocyclic compounds, 24-29 we report herein a highly efficient
route to constructing 3-alkylamino-2-alkyl/aryl/hetero-aryl
indolizine-1-carbonitrile derivatives via [bmim]Cl promoted
one-pot three-component reactions of aldehydes, isocyanides
and 2-pyridylacetonitrile under base and solvent-free condition
at room temperature. The classical synthetic method for
constructing 3-alkylamino-2-alkyl/aryl/hetero-aryl indolizine-1-
carbonitrile derivatives is the reaction of aldehydes, isocyanides
and 2-pyridylacetonitrile in the presence of 1, 4-diazabicyclo
[2.2.2] octane and volatile organic solvent such n-butanol at 100
0C temperature was previously reported.30-31 Although, these
synthetic methods create important contributions to the
synthesis of 3-alkylamino-2-alkyl/aryl/hetero-aryl indolizine-1-
carbonitrile derivatives, but they often require skin
corrosive/eye irritative toxic 1, 4-diazabicyclo [2.2.2] octane as
base with volatile organic solvent n-butanol at higher
temperature. Instead of these methods, our approach for the
synthesis indolizine-1-carbonitrile derivatives via [bmim]Cl
promoted one-pot three-component reactions is very simple,
efficient, no any waste formation, milder condition and
Cl
Condition
Time
(h)
Yieldb
(%)
Entry Catalyst(equiv)
/Solvent
----
RT
50 0C
80 0C
120 0C
RT
50 0C
80 0C
120 0C
RT
24
20
16
10
40 min
30 min
30 min
20 min
60 min
60 min
60 min
----
----
----
----
96
92
90
87
50
65
78
1
----
2
----
3
----
4
[bmim]Cl (1)
[bmim]Cl (1)
[bmim]Cl (1)
[bmim]Cl (1)
[bmim]Cl (0.2)
[bmim]Cl (0.5)
[bmim]Cl (0.7)
5
6
7
8
9
10
11
RT
RT
aReactions and conditions: 2-pyridylacetonitrile (1 mmol), 4-
chlorobenzaldehyde (1 mmol), tert butyl isocyanide (1 mmol),
bIsolated yields.
To avoid various volatile organic solvents and clarify the clean
process, the reaction of 2-pyridylacetonitrile (1a) with 4-
chlorobenzaldehyde (2a) and tert butyl isocyanide (3a)
conducted in the 1-butyl-3-methylimidazolium chloride
[bmim]Cl. Surprisingly, the yield of corresponding product 4a
were obtained 96% within 40 min at room temperature (Table
1, entry 5). Second, we performed the reaction at different
temperatures in [bmim]Cl (Table 1, entries 6, 7, 8). The results
revealed that raising the temperature and decreased the
reaction time was disadvantageous for the reaction. Finally, we
also studied the amount of [bmim]Cl for this one pot reaction
and found that 1 equivalent of [bmim]Cl is the optimum amount
to obtain the highest yield of the target compound 4a (Table 1,
entries 5, 9, 10, 11) at room temperature.
produces excellent yields (Scheme 1).
Previous Work
Toxic waste
O
10% DBU
n-Butanol
100 0C, 16hrs
Use of Base & Volatile Organic Solvent
Long reaction time
CN
N
CN
C
N
R1
H
N
R2
R2
N
R2
flash chromatography-Recrystallization
H
This work
O
[bmim]Cl
base, metal-free
CN
N
CN
C
N
RT
broad substrate scope & high yields
simple & mild conditions
No chromatography
R1
H
N
R2
R2
40-60 min
N
R2
H
No waste
To develop the diversity orientated of 3-alkylamino-2-
alkyl/aryl/hetero-aryl indolizine-1-carbonitrile derivatives, we
further investigated the scope and generality of use of various
substituted aryl/heteroaryl/aliphatic aldehydes in the presence
of 2-pyridylacetonitrile and tert butyl isocyanide/cyclohexyl
isocyanide under optimal conditions and the results are listed in
Table 2. The results revealed that the various substituted aryl
aldehydes proceeded the reaction smoothly and gave the
products in good yields. Furthermore, heteroaryl aldehydes was
tested for this one pot reaction. The results shows that, as
compared to various substituted aryl aldehydes, the heteroaryl
aldehydes gave relatively lower yields of corresponding target
molecules. In contract with aromatic heteroaryl aldehydes,
aliphatic aldehyde gave relatively higher yields of the
Scheme 1. Synthesis 3-alkylamino-2-alkyl/aryl/hetero-aryl
indolizine-1-carbonitrile derivatives
Result and discussion-
In exploration of efficient conditions for the non-toxic clean
protocol, the reaction of 2-pyridylacetonitrile (1a) with 4-
chlorobenzaldehyde (2a) and tert butyl isocyanide (3a) under
catalyst and solvent-free conditions at various temperatures
was first investigated (Table 1). Initially by using model
substrate, the reaction was carried at room temperature under
catalyst and solvent-free condition. The result shows that, after
24hrs stirring at room temperature there is no any progress and
TLC indicating starting material as it is (Table 1, entry 1). Then
2 | J. Name., 2012, 00, 1-3
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corresponding 3-alkylamino-2-alkyl/aryl/hetero-aryl indolizine-
1-carbonitril derivatives.
View Article Online
DOI: 10.1039/C9NJ05738B
Interestingly, isophthalaldehyde (5) having a bis aldehyde
Table
2a
Eco-friendly
synthesis
3-alkylamino-2- functionality was also found to be suitable for this reaction to
alkyl/aryl/hetero-aryl indolizine-1-carbonitrile derivativesb
give 2, 2'-(1, 3-phenylene) bis(3-(tert-butylamino)indolizine-1-
carbonitrile) (6) in satisfy to good yields within one hours
(Scheme 2).
O
[bmim]Cl
CN
N
CN
CN
NC
C
N
RT
R1
H
N
R2
O
O
R2
40-60 min
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N
[bmim]Cl
R2
C
N
N
CN
H
H
H
N
HN
N
NH
RT
1
2
3
4
60 min
5
3
1
6, 86%
Scheme 2
5
1
3
6
Reaction of with and to give
CN
N
CN
N
CN
CN
N
N
To prove the path of reaction mechanism of this one pot
process, control experiments were conducted. Firstly, the by
using model substrate the reaction of 4-chlorobenzaldehyde
(2a) and 2-pyridylacetonitrile (1) conducted for the formation of
N
N
N
N
H
H
H
H
4d, 89%
OMe
4a, 96%
4c, 93%
4b, 94%
Cl
F
Knoevenagel
adduct
(Z)-3-(4-chlorophenyl)-2-(pyridin-2-
CN
N
CN
CN
N
N
yl)acrylonitrile 7 in the presence of [bmim]Cl. From this reaction
Knoevenagel adduct 7 was formed in 93% yields (Scheme 3, (1)).
Secondly, the Knoevenagel adduct 7 and tert butyl isocyanide
(3a) was reacted by using [bmim]Cl at room temperature
(Scheme 3, (2)). The targeted compound 3-(tert-butylamino)-2-
(4-chlorophenyl) indolizine-1-carbonitrile 4a was obtained in
96% yields. Furthermore, we study the reaction of 4-
chlorobenzaldehyde (2a) and tert butyl isocyanide (3a) in the
presence of [bmim]Cl. The results reveals that the formation of
N-tert-butyl-2, 5-bis (4-chlorophenyl)-1, 3-dioxol-4-amine 8 in
42% yields with unreacted tert butyl isocyanide (3a) (Scheme 3,
(3)). This study reveals that the reaction was proceed through
Knoevenagel condensation followed by [4+1] cycloaddition.
CN
Br
N
F
N
H
N
H
N
H
N
H
4e, 88%
4f, 91%
OEt
4g, 92%
4h, 90%
Et
CN
CN
N
N
CN
Cl
CN
N
N
N
H
N
H
N
H
N
H
Cl
4l, 95%
4k, 92%
4j, 90%
4i, 87%
CN
N
CN
N
CN
CN
N
N
N
H
N
H
N
N
H
H
N
Ph
4p, 85%
4o, 85%
4n, 87%
4m, 75%
Cl
Scheme 3. Control experiments
O
CN
[bmim]Cl
N
H
(1)
[bmim]Cl
Recycled
H2
0
CN
N
CN
CN
RT
CN
N
N
CN
N
N
Cl
25 min
by product
7, 93%
N
H
2a
1
N
N
N
H
Cl
H
H
4t, 94%
4r, 88%
4s, 85%
4q, 93%
Et
OMe
OEt
F
[bmim]Cl
C
N
3
[bmim]Cl
Recycled
RT
N
CN
CN
(2)
N
15 min
7
N
H
CN
CN
Br
N
N
CN
Cl
N
CN
N
Cl
via [4+1] cycloaddition
4a, 96%
F
Cl
N
H
N
H
N
H
N
H
F
Cl
4w, 83%
4v, 89%
4x, 90%
4u, 91%
O
O
Cl
[bmim]Cl
C
N
3
O
(3)
H
C
N
RT
NH
8, 42%
Cl
40 min
CN
N
CN
CN
unreacted
CN
N
N
N
2a
3
N
H
N
H
N
H
N
H
N
Cl
Based on the above experimental results and on the basis of
literature,32 a tentative reaction pathway for this isocyanides-
based [4 + 1]-cycloaddition reaction is exemplified in Scheme 4.
Initially, Knoevenagel adduct was formed by the action
[bmim]Cl. It is hypothesized that, anion Cl- of the [bmim]Cl has
high hydrogen bond accepting basicity are beneficial in
weakening the H–C bond. Similarly, cations can constitute
complexes with oxygen atoms of the aldehydes, weakening the
C=O bond. It should be pointed out that, among ILs, [bmim]Cl is
often used to promote dehydration of various substrates.33
4aa, 95%
4y, 92%
4ab, 95%
4z, 94%
CN
N
N
CN
N
CN
Ph
N
N
H
N
N
H
H
4ac, 77%
4ad, 86%
4ae, 85%
aReactions and conditions: 2-pyridylacetonitrile (1 mmol),
aldehydes (1 mmol), isocyanides (1 mmol), [bmim]Cl (1 mmol)
bIsolated yields.
This journal is © The Royal Society of Chemistry 20xx
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aIsolated yield
Further, the proceeded by isocyanides-based [4
cycloaddition reaction to form the final product 4.
+ 1]-
View Article Online
DOI: 10.1039/C9NJ05738B
5
6
7
8
N
N
[bmi
m]Cl
Conclusion
[bmi
m]Cl
Cl
In summary, room temperature based ionic liquid [bmim]Cl
promoted domino protocol for the synthesis of 3-alkylamino-2-
alkyl/aryl/hetero-aryl indolizine-1-carbonitrile derivatives
under milder condition has been developed. This protocol is
suitable with a wide range of functional groups and bring
diversity oriented indolizine derivatives in moderate to good
yields. The current protocols indicated a clean reaction, a base
and solvent-free process, easily accessible reactants, and
environmentally friendly reaction conditions with high atom
economy.
H
O
CN
R1
N
-H2O
Knoevenagel
condensation
R1
H
9
C
[4+1] cycloaddition
H
10
11
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2
3
N
N
CN
N
R2
1
CN
CN
N
R2
N
R1
H
R2
N
R1
4
Experimental section
Materials and techniques
tautomerization
Scheme 4. Plausible Reaction Mechanism
Chemicals were purchased from Aldrich, Merck, and Alfa Aesar
chemical companies. The NMR spectra were recorded in
dimethylsulfoxide (DMSO-d6) on a Bruker 500 MHz NMR. High
resolution mass spectra (HRMS) were recorded on a Jeol JMS-
700 mass spectrometer.
General procedure for the synthesis of diversely
functionalized
indolizine-1-carbonitrile 4
To a mixture of 2-pyridylacetonitrile (1 mmol), isocyanides (1
mmol) and aldehydes (1 mmol) was added 100 mol % [bmim]Cl
and the reaction mixture was kept room temperature with
constant stirring for stipulated time (see table 2). After
completion of the reaction as monitored by TLC, the crude
product was extracted with ether. The combined organic layers
were washed with brine solution, and dried over Na2SO4. The
Na2SO4 was filtered off and the solvent was removed under
vacuum. The solid crude product was recrystallized from
ethanol to afford pure compound 4.
Finally, to see whether newly developed synthesis of 3-
alkylamino-2-alkyl/aryl/hetero-aryl indolizine-1-carbonitrile
derivatives is suitable for more practical applications, the
reaction of 2-pyridylacetonitrile (1) with 4-chlorobenzaldehyde
(2a) and tert butyl isocyanide (3a) was carried out in a large
scale, 10 mmol. From this reaction, 4a were obtained 94% in
yields (Scheme 5).
3-alkylamino-2-alkyl/aryl/hetero-aryl
O
N
CN
[bmim]Cl
H
C
N
N
RT
CN
1, 10 mmol
H
N
Cl
2a, 10 mmol
40 min
3, 10 mmol
Cl
4a, 3.043 g, 94%
Scheme 5. Gram-scale synthesis of 4a
From the perspective of clean methods, the reusability reaction
media is also important to fulfill the green metrics. Therefore,
the recovery and reusability of the room temperature ionic
liquid [bmim]Cl was investigated by using model reaction (Table
3). After completion of the reaction as monitored by TLC, the
crude product was precipitated in [bmim]Cl. Due to the
insolubility of [bmim]Cl in organic solvents, the crude product
was extracted from with ether. The recycled [bmim]Cl was
washed with ether and dried under vacuum. Then recovered
[bmim]Cl successively applied for the formation 3-(tert-
butylamino)-2-(4-chlorophenyl) indolizine-1-carbonitrile 4a by
using model reaction. The results reveals that, recycling and
reusability of the [bmim]Cl shows high activity and formed the
target product in excellent yield (Table 3).
The spectral and analytical data of the model representative
compound is given here:
4a:
3-(tert-butylamino)-2-(4-chlorophenyl)
indolizine-1-
carbonitrile
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.56 (d, J
= 10Hz, 1H), 7.78-7.75 (m, 2H), 7.59 (d, J = 10Hz, 1H), 7.56-7.54
(m, 2H), 7.21-7.18 (m, 1H), 6.97-6.94 (m, 1H), 4.63 (s, 1H), 0.85
(s, 9H); 13C NMR (500 MHz, DMSO) δC (ppm) 134.8, 132.7, 132.7,
131.5, 128.9, 126.0, 125.0, 124.7, 123.8, 117.3, 116.9, 113.0,
78.5, 55.9, 30.2. HRMS m/z calcd for C19H18ClN3 [M+] 323.8193,
found 323.8190.
4b: 3-(tert-butylamino)-2-p-tolylindolizine-1-carbonitrile
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.55 (d, J
= 5Hz, 1H), 7.63 (d, J = 10 Hz, 2H), 7.57 (d, J = 10Hz, 1H), 7.28 (d,
J = 10Hz, 2H), 7.16 (t, J = 12Hz, 1H), 6.92 (t, J = 12Hz, 1H), 4.56
(s, 1H), 2.36 (s, 3H), 0.83 (s, 9H); 13C NMR (500 MHz, DMSO) δC
(ppm) 137.1, 134.7, 130.8, 129.6, 129.4, 126.1, 125.7, 124.8,
123.5, 117.6, 116.7, 112.7, 78.7, 55.8, 30.2, 21.2. HRMS m/z
calcd for C20H21N3 [M+] 303.4008, found 303.4002.
Table 3. Recycling and reuse of [bmim]Cl
Entry
Reaction cycle
First (fresh run)
Second cycle
Third cycle
Yielda (%)
1
2
3
4
96
94
92
92
4c:
3-(tert-butylamino)-2-(4-fluorophenyl)
indolizine-1-
carbonitrile
Fourth cycle
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Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.55 (d, J 1H), 6.96-6.93 (m, 1H), 4.13 (s, 1H), 0.82 (s, 9H); 13C NMR (500
= 10Hz, 1H), 7.79-7.76 (m, 2H), 7.58 (d, J = 10Hz, 1H), 7.32 (t, J = MHz, DMSO) δC (ppm) 134.3, 133.6, 133.3, 130.3, 130.0, 127.5,
15Hz, 2H), 7.18-7.15 (m, 1H), 6.94-6.91 (m, 1H), 4.60 (s, 1H), 126.5, 124.8, 123.8, 116.9, 115.9, 112.9, 80.4, 55.3, 29.9. HRMS
0.83 (s, 9H); 13C NMR (500 MHz, DMSO) δC (ppm) 163.0, 161.1, m/z calcd for C19H18ClN3 [M+] 323.8193, found 323.8191.
View Article Online
DOI: 10.1039/C9NJ05738B
134.7, 131.8, 131.7, 130.2, 130.2, 125.9, 125.1, 124.9, 123.7, 4j:
117.4, 116.8, 115.8, 115.7, 112.9, 78.7, 55.7, 30.2. HRMS m/z carbonitrile
calcd for C19H18FN3 [M+] 307.3647, found 307.3643.
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.55 (d, J
4d: 3-(tert-butylamino)-2-(4-methoxyphenyl) indolizine-1- = 10Hz, 1H), 7.85 (s, 1H), 7.70 (d, J = 10Hz, 1H), 7.57 (d, J = 10Hz,
carbonitrile 1H), 7.50 (t, J = 15Hz, 1H), 7.45-7.41 (m, 1H), 7.18 (t, J = 15Hz,
3-(tert-butylamino)-2-(3-chlorophenyl)
indolizine-1-
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Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.54 (d, J 1H), 6.95-6.92 (m, 1H), 4.68 (s, 1H), 0.84 (s, 9H); 13C NMR (500
= 5Hz, 1H), 7.67-7.65 (m, 2H), 7.56 (d, J = 10Hz, 1H), 7.17-7.14 MHz, DMSO) δC (ppm) 150.1, 143.6, 138.2, 135.9, 134.9, 133.6,
(m, 1H), 7.04 (d, J = 10Hz, 2H), 6.93-6.90 (m, 1H), 4.53 (s, 1H), 130.7, 129.3, 128.4, 127.8, 126.2, 124.9, 124.4, 123.9, 117.2,
3.81 (s, 3H), 0.84 (s, 9H); 13C NMR (500 MHz, DMSO) δC (ppm) 113.0, 78.5, 55.8, 30.2. HRMS m/z calcd for C19H18ClN3 [M+]
159.1, 134.6, 130.9, 126.0, 125.9, 125.6, 124.8, 123.4, 117.7, 323.8193, found 323.8195.
116.7, 114.3, 112.7, 78.6, 55.7, 55.5, 30.2. HRMS m/z calcd for 4k: 3-(tert-butylamino)-2-o-tolylindolizine-1-carbonitrile
C20H21N3O [M+] 319.4002, found 319.4007.
4e: 3-(tert-butylamino)-2-(4-ethoxyphenyl) indolizine-1- = 5Hz, 1H), 7.58 (d, J = 10Hz, 1H), 7.38-7.25 (m, 4H), 7.19-7.16
carbonitrile (m, 1H), 6.95-6.92 (m, 1H), 4.25 (s, 1H), 2.30 (s, 3H), 0.80 (s, 9H);
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.54 (d, J
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.53 (d, J 13C NMR (500 MHz, DMSO) δC (ppm) 137.0, 134.3, 133.2, 131.5,
= 10Hz, 1H), 7.66 (d, J = 5Hz, 2H), 7.55 (d, J = 10Hz, 1H), 7.16- 130.5, 128.4, 126.4, 126.1, 126.0, 124.8, 123.4, 117.5, 116.8,
7.13 (m, 1H), 7.02 (d, J = 10Hz, 2H), 6.92-6.89 (m, 1H), 4.53 (s, 112.7, 80.2, 55.1, 30.1, 20.2. HRMS m/z calcd for C20H21N3 [M+]
1H), 4.12-4.04 (m, 2H), 1.34 (t, J = 10Hz, 3H), 0.83 (s, 9H); 13C 303.4008, found 303.4005.
NMR (500 MHz, DMSO) δC (ppm) 158.4, 149.9, 144.9, 138.1, 4l: 3-(tert-butylamino)-2-(4-isopropylphenyl) indolizine-1-
134.6, 130.9, 126.0, 124.8, 123.3, 120.6, 117.7, 116.7, 112.7, carbonitrile
78.6, 63.4, 55.7, 30.2, 15.1. HRMS m/z calcd for C21H23N3O [M+] Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.55 (d, J
333.4268, found 333.4273.
= 10Hz, 1H), 7.66 (d, J = 5Hz, 2H), 7.57 (d, J = 10Hz, 1H), 7.34 (d,
indolizine-1- J = 5Hz, 2H), 7.16 (t, J = 15Hz, 1H), 6.91 (t, J = 15Hz, 1H), 4.56 (s,
1H), 2.95-2.90 (m, 1H), 1.23 (d, J = 10Hz, 6H), 0.83 (s, 9H); 13C
4f:
3-(tert-butylamino)-2-(4-ethylphenyl)
carbonitrile
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.55 (d, J NMR (500 MHz, DMSO) δC (ppm) 148.0, 134.7, 131.2, 129.6,
= 10Hz, 1H), 7.65 (d, J = 10Hz, 2H), 7.57 (d, J = 10Hz, 1H), 7.31 126.7, 126.1, 125.8, 124.8, 123.4, 117.6, 116.7, 112.7, 78.7,
(d, J = 10Hz, 2H), 7.18-7.15 (m, 1H), 6.93-6.90 (m, 1H), 2.67-2.63 55.8, 33.6, 30.2, 24.3. HRMS m/z calcd for C22H25N3 [M+]
(m, 2H), 1.22 (t, J = 15Hz, 3H), 0.83 (s, 9H); 13C NMR (500 MHz, 331.4540, found 331.4544.
DMSO) δC (ppm) 143.4, 134.7, 131.1, 129.6, 128.2, 126.1, 125.8, 4m:
124.8, 123.5, 117.6, 116.7, 112.8, 78.7, 55.8, 30.2, 28.4, 15.9. carbonitrile
HRMS m/z calcd for C21H23N3 [M+] 317.4274, found 317.4270. Pale yellow solid; H NMR (500 MHz, DMSO) δH (ppm) 8.95 (s,
3-(tert-butylamino)-2-(pyridin-3-yl)
indolizine-1-
1
4g:
carbonitrile
3-(tert-butylamino)-2-(2-fluorophenyl)
indolizine-1- 1H), 8.60-8.56 (m, 2H), 8.14-8.12 (m, 1H), 7.60 (d, J = 5Hz, 1H),
7.53-7.51 (m, 1H), 7.22-7.19 (m, 1H), 6.96 (t, J = 10Hz, 1H), 4.64
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.56 (d, J (s, 1H), 0.86 (s, 9H); 13C NMR (500 MHz, DMSO) δC (ppm) 150.1,
= 10Hz, 1H), 7.68-7.65 (m, 1H), 7.60 (d, J = 10Hz, 1H), 7.50-7.46 148.7, 137.0, 135.1, 129.9, 126.4, 125.0, 123.9, 123.9, 122.8,
(m, 1H), 7.38-7.30 (m, 2H), 7.21-7.18 (m, 1H), 6.96-6.93 (m, 1H), 117.0, 116.9, 113.0, 78.7, 55.7, 30.3. HRMS m/z calcd for
4.25 (s, 1H), 0.82 (s, 9H); 13C NMR (500 MHz, DMSO) δC (ppm) C18H18N4 [M+] 290.3623, found 290.3625.
160.8, 158.9, 134.5, 132.8, 130.7, 130.6, 126.6, 124.9, 123.8, 4n: 3-(tert-butylamino)-2-isopropylindolizine-1-carbonitrile
121.4, 121.3, 120.3, 116.8, 116.2, 116.1, 112.9, 80.0, 55.5, 29.9. Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.38 (d, J
HRMS m/z calcd for C19H18FN3 [M+] 307.3647, found 307.3644. = 5Hz, 1H), 7.45 (d, J = 10Hz, 1H), 7.08-7.04 (m, 1H), 6.82-6.79
4h: 2-(2-bromophenyl)-3-(tert-butylamino) indolizine-1- (m, 1H), 4.42 (s, 1H), 3.31-3.22 (m, 1H), 1.34 (d, J = 10Hz, 6H),
carbonitrile
1.10 (s, 9H); 13C NMR (500 MHz, DMSO) δC (ppm) 135.3, 131.9,
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.55 (d, J 124.9, 122.7, 118.0, 116.3, 112.0, 76.3, 55.0, 30.3, 25.2, 23.1.
= 5Hz, 1H), 7.77 (d, J = 10Hz, 1H), 7.60-7.56 (m, 2H), 7.50-7.47 HRMS m/z calcd for C16H21N3 [M+] 255.3580, found 255.3581.
(m, 1H), 7.37-7.34 (m, 1H), 7.19-7.16 (m, 1H), 6.95-6.92 (m, 1H), 4o: 3-(tert-butylamino)-2-phenethylindolizine-1-carbonitrile
1
4.08 (s, 1H), 0.84 (s, 9H); 13C NMR (500 MHz, DMSO) δC (ppm) Yellow solid; H NMR (500 MHz, DMSO) δH (ppm) 8.40 (d, J =
134.6, 134.3, 133.4, 133.1, 130.4, 128.0, 126.3, 125.5, 124.8, 10Hz, 1H), 7.50 (d, J = 5Hz, 1H), 7.33-7.26 (m, 4H), 7.22-7.19 (m,
124.3, 123.7, 117.1, 116.9, 112.9, 80.5, 55.3, 30.0. HRMS m/z 1H), 7.11-7.07 (m, 1H), 6.85-6.82 (m, 1H), 4.24 (s, 1H), 3.06-2.96
calcd for C19H18BrN3 [M+] 368.2703, found 368.2705.
4i: 3-(tert-butylamino)-2-(2-chlorophenyl)
carbonitrile
(m, 4H), 1.10 (s, 9H); 13C NMR (500 MHz, DMSO) δC (ppm) 141.9,
indolizine-1- 134.6, 128.9, 128.6, 126.5, 126.3, 125.2, 124.8, 122.9, 117.6,
116.5, 112.1, 78.9, 55.4, 36.1, 30.3, 28.0. HRMS m/z calcd for
1
yellow solid; H NMR (500 MHz, DMSO) δH (ppm) 8.55 (d, J = C21H23N3 [M+] 317.4274, found 317.4276.
10Hz, 1H), 7.62-7.57 (m, 3H), 7.47-7.43 (m, 2H), 7.21-7.17 (m,
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4p: 2-(4-chlorophenyl)-3-(cyclohexylamino) indolizine-1- 2H), 7.13 (t, J = 15Hz, 1H), 6.93 (t, J = 15Hz, 1H), 4.54 (d, J = 5Hz,
View Article Online
DOI: 10.1039/C9NJ05738B
carbonitrile
1H), 2.64-2.61 (m, 1H), 1.57-1.46 (m, 4H), 1.36-1.32 (m, 1H),
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.42 (d, J 1.01-0.88 (m, 5H); 13C NMR (500 MHz, DMSO) δC (ppm) 160.9,
= 5Hz, 1H), 8.40 (d, J = 10Hz, 2H), 7.60-7.55 (m, 3H), 7.17 (t, J = 158.9, 134.0, 132.6, 130.6, 130.5, 128.1, 124.9, 123.9, 123.0,
15Hz, 1H), 6.95 (t, J = 10Hz, 1H), 4.82 (d, J = 5Hz, 1H), 2.66-2.62 120.6, 120.5, 117.0, 116.9, 116.2, 116.0, 115.9, 113.0, 79.7,
(m, 1H), 1.59-1.53 (m, 4H), 1.40-1.38 (m, 1H), 1.07-0.97 (m, 5H); 55.5, 33.4, 25.6, 24.5. HRMS m/z calcd for C21H20FN3 [M+]
13C NMR (500 MHz, DMSO) δC (ppm) 134.6, 132.6, 131.9, 130.8, 333.4020, found 333.4023.
129.0, 127.6, 124.1, 123.4, 121.0, 117.4, 117.0, 113.3, 78.0, 4v: 2-(2-bromophenyl)-3-(cyclohexylamino) indolizine-1-
56.1, 33.6, 25.7, 24.6. HRMS m/z calcd for C21H20ClN3 [M+] carbonitrile
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349.8566, found 349.8567.
4q: 3-(cyclohexylamino)-2-(4-fluorophenyl) indolizine-1- = 10Hz, 1H), 7.78 (d, J = 10Hz, 1H), 7.58 (d, J = 10Hz, 1H), 7.52-
carbonitrile 7.48 (m, 2H), 7.40-7.36 (m, 1H), 7.13 (t, J = 15Hz, 1H), 6.93 (t, J
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.36 (d, J
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.41 (d, J = 15Hz, 1H), 4.52 (d, J = 5Hz, 1H), 2.61-2.57 (m, 1H), 1.60-1.46
= 5Hz, 1H), 7.82-7.80 (m, 2H), 7.58 (d, J = 5Hz, 1H), 7.33 (t, J = (m, 4H), 1.39-1.36 (m, 1H), 1.05-0.83 (m, 5H); 13C NMR (500
15Hz, 2H), 7.14 (t, J = 15Hz, 1H), 6.93 (t, J = 15Hz, 1H), 4.79 (d, J MHz, DMSO) δC (ppm) 134.1, 133.5, 133.2, 132.9, 130.5, 128.0,
= 5Hz, 1H), 2.64-2.61 (m, 1H), 1.56-1.49 (m, 4H), 1.38-1.34 (m, 124.7, 123.9, 122.7, 120.3, 117.1, 113.0, 80.2, 55.3, 33.5, 33.4,
1H), 1.08-0.93 (m, 5H); 13C NMR (500 MHz, DMSO) δC (ppm) 25.7, 24.6. HRMS m/z calcd for C21H20BrN3 [M+] 394.3076,
162.9, 161.0, 134.4, 131.1, 131.0, 129.3, 127.4, 124.0, 123.2, found 394.3079.
121.5, 117.5, 117.0, 116.0, 115.8, 113.1, 78.2, 56.0, 33.6, 25.7, 4w: 2-(2-chlorophenyl)-3-(cyclohexylamino) indolizine-1-
24.6. HRMS m/z calcd for C21H20FN3 [M+] 333.4020, found carbonitrile
333.4028.
4r: 3-(cyclohexylamino)-2-(4-methoxyphenyl) indolizine-1- = 5Hz, 1H), 7.63-7.45 (m, 5H), 7.13 (t J = 15Hz, 1H), 6.93 (t, J =
carbonitrile 15Hz, 1H), 4.52 (d, J = 5Hz, 1H), 2.61-2.57 (m, 1H), 1.56-1.35 (m,
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.35 (d, J
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.40 (d, J 5H), 1.08-0.83 (m, 5H); 13C NMR (500 MHz, DMSO) δC (ppm)
= 5Hz, 1H), 7.72 (d, J = 5Hz, 2H), 7.56 (d, J = 10Hz, 1H), 7.14-7.10 133.9, 133.6, 133.1, 132.0, 130.3, 129.8, 128.1, 127.5, 123.9,
(m, 1H), 7.06 (d, J = 10Hz, 2H), 6.93-6.90 (m, 1H), 4.71 (d, J = 122.8, 118.7, 117.1, 116.9, 113.0, 80.1, 55.2, 33.4, 25.7, 24.5.
5Hz, 1H), 3.81 (s, 3H), 2.66-2.63 (m, 1H), 1.57-1.50 (m, 4H), 1.40- HRMS m/z calcd for C21H20ClN3 [M+] 349.8566, found 349.8571.
1.36 (m, 1H), 1.09-0.92 (m, 5H); 13C NMR (500 MHz, DMSO) δC 4x: 3-(cyclohexylamino)-2-(3-fluorophenyl) indolizine-1-
(ppm) 159.0, 134.3, 130.2, 126.9, 125.1, 123.9, 122.9, 122.4, carbonitrile
117.7, 116.8, 114.4, 113.0, 78.1, 55.9, 55.5, 33.6, 25.7, 24.6. Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.42 (d, J
HRMS m/z calcd for C22H23N3O [M+] 345.4375, found 345.4371. = 5Hz, 1H), 7.64-7.51 (m, 4H), 7.22-7.14 (m, 2H), 6.94 (t, J =
4s: 3-(cyclohexylamino)-2-(4-ethoxyphenyl) indolizine-1- 15Hz, 1H), 4.74 (d, J = 5Hz, 1H), 2.72-2.68 (m, 1H), 1.60-1.53 (m,
carbonitrile
4H), 1.43-1.39 (m, 1H), 1.13-0.97 (m, 5H); 13C NMR (500 MHz,
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.39 (d, J DMSO) δC (ppm) 163.6, 161.7, 135.5, 135.4, 134.6, 130.8, 130.8,
= 5Hz, 1H), 7.70 (d, J = 10Hz, 2H), 7.56 (d, J = 5Hz, 1H), 7.12 (t, J 127.8, 125.2, 125.2, 124.0, 123.3, 121.0, 117.2, 117.0, 115.7,
= 15Hz, 1H), 7.03 (d, J = 10Hz, 2H), 6.91 (t, J = 15Hz, 1H), 4.70 (d, 115.5, 114.6, 114.4, 113.2, 78.3, 56.2, 33.6, 25.7, 24.6. HRMS
J = 5Hz, 1H), 4.09-4.05 (m, 1H), 2.66-2.62 (m, 1H), 1.57-1.50 (m, m/z calcd for C21H20FN3 [M+] 333.4020, found 333.4021.
4H), 1.36-1.34 (m, 4H), 1.08-0.92 (m, 5H); 13C NMR (500 MHz, 4y: 2-(3-chlorophenyl)-3-(cyclohexylamino) indolizine-1-
DMSO) δC (ppm) 158.3, 134.3, 130.2, 126.9, 125.0, 123.9, 122.8, carbonitrile
122.4, 117.8, 116.8, 114.8, 112.9, 78.1, 63.4, 55.9, 33.6, 25.7, Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.43 (d, J
24.6, 14.1. HRMS m/z calcd for C23H25N3O [M+] 359.4641, found = 5Hz, 1H), 7.88 (d, J = 5Hz, 1H), 7.74 (d, J = 5Hz, 1H), 7.59 (d, J
359.4639.
= 5Hz, 1H), 7.52 (t, J = 15Hz, 1H), 7.43 (d, J = 10Hz, 1H), 7.17 (t, J
indolizine-1- = 15Hz, 1H), 6.95 (t, J = 15Hz, 1H), 4.89 (d, J = 5Hz, 1H), 2.65-
2.62 (m, 1H), 1.58-1.51 (m, 4H), 1.41-1.37 (m, 1H), 1.11-0.93 (m,
4t:
3-(cyclohexylamino)-2-(4-ethylphenyl)
carbonitrile
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.41 (d, J 5H); 13C NMR (500 MHz, DMSO) δC (ppm) 135.1, 134.6, 133.7,
= 5Hz, 1H), 7.69 (d, J = 5Hz, 2H), 7.57 (d, J = 5Hz, 1H), 7.32 (d, J 130.8, 128.5, 127.8, 127.6, 124.1, 123.5, 120.5, 117.3, 117.1,
= 5Hz, 2H), 7.14-7.11 (m, 1H), 6.92 (t, J = 15Hz, 1H), 4.74 (d, J = 113.3, 78.0, 55.2, 33.7, 25.7, 24.6. HRMS m/z calcd for
5Hz, 1H), 2.68-2.63 (m, 2H), 1.57-1.49 (m, 4H), 1.39-1.37 (m, C21H20ClN3 [M+] 349.8566, found 349.8569.
1H), 1.22 (t, J = 15Hz, 3H), 1.09-0.91 (m, 5H); 13C NMR (500 MHz, 4z: 3-(cyclohexylamino)-2-p-tolylindolizine-1-carbonitrile
DMSO) δC (ppm) 143.3, 134.4, 130.3, 128.7, 128.3, 127.2, 123.9, Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.41 (d, J
122.9, 122.4, 117.7, 116.9, 113.0, 78.2, 56.0, 33.6, 28.4, 25.7, = 5Hz, 1H), 7.67 (d, J = 10Hz, 2H), 7.57 (d, J = 5Hz, 1H), 7.29 (d, J
24.6, 15.8. HRMS m/z calcd for C23H25N3 [M+] 343.4647, found = 10Hz, 2H), 7.13 (t, J = 15Hz, 1H), 6.92 (t, J = 15Hz, 1H), 4.73 (d,
343.4653.
4u: 3-(cyclohexylamino)-2-(2-fluorophenyl) indolizine-1- 1.39-1.36 (m, 1H), 1.09-0.93 (m, 5H); 13C NMR (500 MHz, DMSO)
carbonitrile δC (ppm) 137.1, 134.4, 130.0, 129.6, 128.9, 127.2, 123.9, 123.0,
J = 5Hz, 1H), 2.67-2.63 (m, 1H), 2.35 (s, 3H), 1.56-1.50 (m, 4H),
1
Yellow solid; H NMR (500 MHz, DMSO) δH (ppm) 8.37 (d, J = 122.4, 117.7, 116.9, 113.0, 78.2, 56.0, 33.6, 25.7, 24.6, 21.3.
5Hz, 1H), 7.64-7.58 (m, 2H), 7.50-7.46 (m, 1H), 7.38-7.31 (m, HRMS m/z calcd for C22H23N3 [M+] 329.4381, found 329.4387.
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4aa: 3-(cyclohexylamino)-2-(4-isopropylphenyl) indolizine-1- 112.8, 79.2, 55.9, 30.3. HRMS m/z calcd for C32H32N6
DOI: 10.1039/C9NJ05738B
carbonitrile
500.6367, found 500.6370.
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.40 (d, J
= 10Hz, 1H), 7.71 (d, J = 5Hz, 2H), 7.56 (d, J = 10Hz, 1H), 7.34 (d, References
J = 10Hz, 2H), 7.12 (t, J = 15Hz, 1H), 6.90 (t, J = 15Hz, 1H), 4.74 1. J. P. Michael, Nat. Prod. Rep. 2008, 25, 139.
(d, J = 5Hz, 1H), 2.95-2.89 (m, 1H), 2.67-2.63 (m, 1H), 1.57-1.49 2. C. Bailly, Curr. Med. Chem.: Anti-Cancer Agents 2004, 4, 363.
(m, 4H), 1.39-1.35 (m, 1H), 1.23 (d, J = 10Hz, 6H), 1.10-0.90 (m, 3. A. K. Das, S. Som, Orient. J. Chem. 2006, 2, 415.
5H); 13C NMR (500 MHz, DMSO) δC (ppm) 147.9, 134.4, 130.4, 4. S. Lingala, R. Nerella, R. Cherukupally, A. K. Das, Int. J. Pharm.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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30
31
32
33
34
35
36
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128.9, 127.2, 126.8, 123.9, 122.9, 122.3, 117.7, 116.9, 113.0,
78.2, 56.0, 33.7, 33.6, 25.7, 24.6, 24.2. HRMS m/z calcd for 5. P. Sharma, A. Kumar, S. Sharma, N. Rane, Bioorg. Med. Chem.
Sci. Rev. Res. 2011, 6, 128.
C24H27N3 [M+] 357.4913, found 357.4910.
4ab: 3-(cyclohexylamino)-2-(pyridin-2-yl)
carbonitrile
Lett. 2005, 15, 937.
indolizine-1- 6. S. Teklu, L. L. Gundersen, F. Riseand, M. Tilset, Tetrahedron,
2005, 61, 4643.
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.69 (d, J 7. A. Hazra, S. Mondal, A. Maity, S. Naskar, P. Saha, R. Paira,
= 5Hz, 1H), 8.24 (d, J = 10Hz, 1H), 8.03-7.93 (m, 2H), 7.60 (d, J =
10Hz, 1H), 7.34 (t, J = 10Hz, 1H), 7.15 (t, J = 15Hz, 1H), 6.94 (t, J
= 15Hz, 1H), 6.18 (d, J = 10Hz, 1H), 2.96-2.91 (m, 1H), 1.68-1.41 8. T. Weide, L. Arve, H. Prinz, H. Waldmann, H. Kessler,
(m, 5H), 1.15-0.99 (m, 5H); 13C NMR (500 MHz, DMSO) δC (ppm)
Bioorganic & Medicinal Chemistry Letters, 2006, 16, 59.
152.5, 149.5, 137.7, 134.9, 131.3, 124.1, 123.2, 122.4, 121.9, 9. J. Wan, C. J. Zheng, M. K. Fung, X.K. Liu, C. S. Lee, X. H. Zhang,
K. B. Sahu, P. Paira, S. Ghosh, C. Sinha, A. Samanta, S.
Banerjee, N. B. Mondal, Eur. J. Med. Chem. 2011, 46, 2132.
117.7, 117.5, 116.3, 113.6, 76.8, 55.2, 33.7, 25.6, 24.7. HRMS
m/z calcd for C20H20N4 [M+] 316.3996, found 316.3998.
J. Mater. Chem. 2012, 22, 4502.
10. (a) S. C. Smith, E. D. Clarke, S. M. Ridley, D. Bartlett, D. T.
Greenhow, H. Glithro, A. Y. Klong, G. Mitchell, G. W. Mullier,
Pest Manage. Sci. 2005, 61, 16−24; (b) G. Mitchell, S. C.
Smith, E. D. Clarke, U. K. Zeneca, US Patent 92191410, 1994.
4ac:
carbonitrile
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.97 (s,
3-(cyclohexylamino)-2-(pyridin-3-yl)
indolizine-1-
1H), 8.60 (dd, J = 5, 5Hz, 1H), 8.42 (d, J = 10Hz, 1H), 8.15 (t, J = 11. M. Birch, G. E. M. Sibley, D. Law, J. D. Oliver, World Patent,
10Hz, 1H), 7.60 (d, J = 10Hz, 1H), 7.54-7.51 (m, 1H), 7.19-7.16 WO2009144473A1, 2009.
(m, 1H), 6.97-6.94 (m, 1H), 4.81 (d, J = 5Hz, 1H), 2.71-2.67 (m, 12. (a) K. H. Oh, S. M. Kim, S. Y. Park, J. K. Park, Org. Lett. 2016,
1H), 1.59-1.52 (m, 4H), 1.42-1.38 (m, 1H), 1.11-0.95 (m, 5H); 13
C
18, 2204; (b) X. Meng, P. Liao, J. Liu, X. Bi, Chem. Commun.
2014, 50, 11837; (c) L. Zhang, X. Li, Y. Liu, D. Zhang, Chem.
Commun. 2015, 51, 6633.
NMR (500 MHz, DMSO) δC (ppm) 149.6, 148.7, 136.3, 134.8,
129.1, 127.9, 124.1, 123.9, 123.4, 119.3, 117.1, 113.3, 78.3,
56.1, 33.6, 25.7, 24.6. HRMS m/z calcd for C20H20N4 [M+] 13. (a) D. Chandra Mohan, C. Ravi, V. Pappula, S. Adimurthy, J.
316.3996, found 316.3998.
4ad: 3-(cyclohexylamino)-2-isopropylindolizine-1-carbonitrile
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.18 (d, J
= 5Hz, 1H), 7.47 (d, J = 10Hz, 1H), 7.05 (t, J = 15Hz, 1H), 6.84 (t, J
Org. Chem. 2015, 80, 6846; (b) M. Kucukdisli, T. Opatz, Eur.
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13200.
= 15Hz, 1H), 4.58 (s, 1H), 3.28-3.23 (m, 1H), 2.71-2.68 (m, 1H), 14. (a) F. Li, J. Chen, Y. Hou, Y. Li, X. Y. Wu, X. Tong, Org. Lett.
1.77-1.65 (m, 4H), 1.54-1.51 (m, 1H), 1.34 (d, J = 5Hz, 6H), 1.25-
1.05 (m, 5H); 13C NMR (500 MHz, DMSO) δC (ppm) 134.7, 129.5,
126.2, 123.9, 122.2, 117.9, 116.5, 112.4, 76.0, 56.5, 33.9, 25.9,
25.0, 23.2. HRMS m/z calcd for C18H23N3 [M+] 281.3953, found
281.3955.
4ae: 3-(cyclohexylamino)-2-phenethylindolizine-1-carbonitrile
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.20 (d, J
= 5Hz, 1H), 7.51 (d, J = 10Hz, 1H), 7.30-7.17 (m, 5H), 7.06 (t, J =
15Hz, 1H), 6.84 (t, J = 15Hz, 1H), 4.43 (d, J = 5Hz, 1H), 2.97 (s,
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134.0, 128.8, 128.7, 127.8, 126.4, 123.8, 122.6, 122.3, 117.5,
116.7, 112.5, 78.6, 56.6, 36.3, 27.4, 25.8, 25.0. HRMS m/z calcd
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696; (c) F. Wang, Y. Shen, H. Hu, X. Wang, H. Wu, Y. Liu, J.
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carbonitrile)
Pale yellow solid; 1H NMR (500 MHz, DMSO) δH (ppm) 8.56 (d, J
= 10Hz, 2H), 7.97 (s, 1H), 7.74 (d, J = 10Hz, 2H), 7.61-7.58 (m, 18. (a) C. C. Razvan, E. Ruijter, R. V. A. Orru, Green Chem.,
3H), 7.19 (t, J = 15Hz, 2H), 6.94 (t, J = 15Hz, 2H), 4.45 (s, 2H), 0.90
(s, 18H); 13C NMR (500 MHz, DMSO) δC (ppm) 134.8, 134.1,
130.6, 129.1, 128.8, 126.3, 126.1, 124.9, 123.5, 117.3, 116.8,
2014,16, 2958; (b) G. Yanlong, Green Chem., 2012,14, 2091;
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